This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Beta-D-Dioxolane-2,6-diaminopurine (DAPD) is the prodrug of beta-D-dioxolane guanosine (DXG). DAPD has potent, selective in vitro activity against several clinically important, resistant HIV mutants. The average oral bioavailability of DAPD/DXG after DAPD oral administration, in humans and monkeys, is approximately 30%, which suggests other prodrugs be developed to maximize oral bioavailability and effectiveness. Recently, a dose-ranging efficacy and pharmacokinetic study was conducted with D-2-aminopurine-dioxolane (APD), another prodrug of DXG, in woodchucks chronically infected with woodchuck hepatitis virus (WHV). The 30 mg/kg per day dose resulted in a more pronounced, statistically significant decline in serum WHV viremia of 1.9 log10 copies/ml and was associated with a 1.5-fold reduction in hepatic WHV DNA. For safety studies, complete blood counts and serum biochemical measurements were performed prior to treatment, at the end of week 4 and at four and twelve weeks following drug withdrawal. No clinical signs of toxicity were observed in APD-treated woodchucks given up to 30 mg/kg doses for 4 weeks and after 12 weeks of post-treatment. Efficacy and safety results suggested that APD could also be an option to deliver DXG in humans. A single dose of intravenous (iv) APD in monkeys was warranted, since their PK profile mimics that observed in humans for most of the nucleoside analogs. Three rhesus monkeys were used for a pharmacokinetic study for APD. Preliminary results indicate that the average Cmax and Tmax for APD were 85.13 mM and 0.25 h, and for DXG were 104.6 mM and 0.33 h, respectively. The average serum beta half-lives for APD and DXG were 1.31 and 3.81h, respectively, suggesting rapid conversion of APD into DXG following APD iv administration. Therefore, further studies are warranted to determine its fate as a DXG prodrug.